1. Field of the Invention
This invention relates to magnetic resonance imaging (MRI) of the human body and to the use of paramagnetic contrast agents to improve the diagnostic usefulness of the MR images. More particularly, this invention is concerned with paramagnetic oil emulsions as enteric MRI contrast agents and their use in MRI evaluation of the abdomen and pelvis.
2. Description of the Prior Art
Magnetic resonance imaging is a useful diagnostic tool due to its good tissue differentiation. The imaging is enhanced by use of paramagnetic contrast agents which affect the relaxation times T1 (spin-lattice) and T2 (spin-spin) of hydrogen atoms present in the body materials. In abdominal MRI, bowel loops and intraluminal contents can mimic pathology such as adenopathy, pancreatic or other retroperitoneal lesions. Therefore, the development of a reliable oral MRI contrast agent is required before gastrointestinal MRI can assume a major role clinically.
Current review articles indicate that a problem in gastrointestinal tract MRI examinations has been stimulation of peristalsis, lack of contrast, and the lack of acceptable oral contrast agents. Particularly, magnetic contrast agents have not been developed for small bowel lumen. Clanton, Jeffrey A., "Oral Contrast Agents," Magnetic Resonance Imaging, Vol. I, Chap. 48, pp. 830-837, W. B. Saunders Company (1988). Stark, David D. and Bradley, William G., Jr., "Gastrointestinal Contrast Agents," Magnetic Resonance Imaging, pp. 1134-1139, The C. V. Mosby Company, St. Louis, Mo. (1988).
In the past few years, a variety of agents have been advocated as potential oral MRI contrast agents. However, none of them satisfies all the criteria of a satisfactory agent including: uniform effect throughout the gastrointestinal tract; good patient acceptance; no side effects; and ability to mix freely with intestinal contents. The potential oral MRI contrast agents that have been proposed can be divided into four different categories.
The first group includes miscible positive agents, such as MnCL.sub.2, Burnett, K. R., Goldstein, E. J., Wolf, G. L., Sen, S., and Mamourian, A. C., "The Oral Administration of MnCl.sub.2 : A Potential Alternative to IV Injection for Tissue Contrast Enhancement in Magnetic Resonance Imaging," Magnetic Resonance Imaging, Vol. 2, pp. 307-314, Pergamon Press, Ltd. (1984); Mamourian, A. C., Burnett, K. R., Goldstein, E. J., Wolf, G. L., Kressel, H. Y. and Baum, S., "Proton Relaxation Enhancement in Tissue Due to Ingested Manganese Chloride: Time Course and Dose Response in the Rat," Physiological Chemistry and Physics and Medical NMR, 16, pp. 123-128 (1984); dilute iron aqueous solutions such as Geritol.RTM., ferric ammonium citrate, Wesbey, G. E., Brasch, R. C., Goldberg, H. I., and Engelstad, B. L., "Dilute Oral Iron Solutions as Gastrointestinal Contrast Agents for Magnetic Resonance Imaging; Initial Clinical Experience," Magnetic Resonance Imaging, Vol. 3, pp. 57-64 (1985); metal chelates, Runge, V. M., Stewart, R. G., Clanton, J. A., Jones, M. M., Lukehart, C. M., Partain, C. L., and James, A. E., Jr., "Work in Progress: Potential Oral and Intravenous Paramagnetic NMR Contrast Agents," Radiology, Vol. 147, No. 3, pp. 789-791 (June, 1983); and Gd-DTPA with mannitol, Laniado, M., Kornmesser, W., Hamm, B., Clauss, W., Weinmann, H. J., and Felix, R., "MR Imaging of the Gastrointestinal Tract: Value of Gd-DTPA," Amer. Jour. of Roentgenology, 150:817-821 (April, 1988). Oral contrast agents in aqueous solutions including osmotically active material, such as mannitol, are taught by U.S. Pat. No. 4,719,098. The disadvantages of these agents include significant dilutional effect from gastric, biliary and pancreatic secretions in the proximal small bowel resulting in failure to show effects distal to the ligament of Treitz, patient non-acceptance of metallic taste, complex absorptive process in the distal small bowel resulting in unpredictable and varying concentrations in the GI tract, and in the case of Gd-DTPA with mannitol some patients experienced diarrhea, probably due to the osmotic effect of mannitol.
The second group includes immiscible negative agents such as ferrite particles, Widder, D. J., Edelman, R. R., Grief, W. L. and Monda, L., "Magnetite Albumin Suspension: A Superparamagnetic Oral MR Contrast Agent," Amer. Jour. of Roentgenology, 149:839-843 (October, 1987); Hahn, P. F., Stark, D. D., Saini, S., Lewis, J. M., Wittenberg, J., and Ferrucci, J. T., "Ferrite Particles for Bowel Contrast in MR Imaging: Design Issues and Feasibility Studies," Radiology, 164, pp. 37-41 (July , 1987). Micellular particles such as phospholipid vesicles enclosing a paramagnetic material as contract agents for NMR imaging is taught by U.S. Pat. No. 4,728,575. These vesicles are targeted to accumulate in tumor tissue after intravenous injection. Aqueous suspensions of particles of water insoluble paramagnetic compounds suitable for oral or rectal administration for gastrointestinal NMR are taught by U.S. Pat. 4,615,879. Superparamagnetic metal oxides coated with polysaccharides are taught to be biologically degradable and a contrast agent for MRI by U.S. Pat. No. 4,827,945. The disadvantages of this group include the fact that with high concentrations, the homogeneity of the magnetic field may be distorted and produce image artifacts. This is especially detrimental in gradient echo imaging.
The third group includes immiscible positive agents such as aqueous oil emulsions, Li, K.C.P., Tart, R. P., Storm, B., Rolfes, R., Ang, P., and Ros, P. R., "MRI Oral Contrast Agents: Comparative Study of Five Potential Agents in Humans," Proceedings of the Eighth Annual Meeting of the Society of Magnetic Resonance in Medicine, Amsterdam, Aug. 18, 1989, p. 791. The major disadvantage of this group is that even with very concentrated oil emulsions, the enhancement effect is not adequate when T1 weighted pulse sequences are used.
The fourth group includes immiscible negative agents such as CO.sub.2 gas tablets, Weinreb, J. C., Maravilla, K. R., Redman, H. C., and Nunnally, R., "Improved MR Imaging of the Upper Abdomen with Glucagon and Gas," J. Comput. Assist., Tomogr. 8, pp. 835-838 (1984), perfluorocarbons, Mattrey, R. F., Hajek, P. C., Gylys-Morin, V. M., Baker, L. L., Martin, J., Long, D. C., and Long, D. M., "Perfluorochemicals as Gastrointestinal Contrast Agents for MR Imaging: Preliminary Studies in Rats and Humans, Amer. Jour. of Roentgenology, 148, pp. 1259-1263 (June, 1987); Mattrey, R. F., Perfluorooctylbromide: A New Contrast Agent for CT, Sonography, and MR Imaging," Amer. Jour. of Roentgenology. 152:247-252 (February, 1989), and kaolin-pectin, Li, K.C.P., Tart, R. P., Storm, B., Rolfes, R., Ang, P., and Ros, P. R., supra. This group has high potentials. However, CO.sub.2 is limited to applications to the proximal GI tract. Perfluorocarbons are not FDA approved yet for clinical use and kaolin-pectin may cause severe constipation in the dosages suggested.